Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation.
Abnormalities in cultured fibroblasts from familial Alzheimer's Disease (FAD) cases uniquely enable the determination of how gene defects alter cell biology in living tissue from affected individuals. The current study focused on measures of calcium regulation and oxidative metabolism in fibroblast lines from controls and FAD individuals with the Swedish APP670/671 mutation. Bombesin-induced elevations in calcium in APP670/671 mutation-bearing lines were reduced by 40% (p < 0.05), a striking contrast to the 100% increase seen in sporadic AD and presenilin-1 (PS1) mutation-bearing cells in previously published studies. The APP670/671 mutation-bearing lines did not exhibit the exaggerated 4-bromo-A23187 releasable pool of calcium following 10 nM bradykinin, the enhanced sensitivity of calcium stores to low concentrations of bradykinin, nor the reduced activity of alpha-ketoglutarate dehydrogenase previously reported in cells from sporadic AD and mutant PS1 FAD. Thus, an altered regulation of internal calcium stores is common to all AD lines, but the calcium pool affected and the polarity of the alteration varies, apparently in association with particular gene mutations. Comparison of signal transduction in cell lines from multiple, genetically characterized AD families will allow testing of the hypothesis that these various pathogenic FAD abnormalities that lead to AD converge at the level of abnormal signal transduction.
Gibson
G E
GE
Cornell University Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA. ggibson@med.cornell.edu
Vestling
M
M
Zhang
H
H
Szolosi
S
S
Alkon
D
D
Lannfelt
L
L
Gandy
S
S
Cowburn
R F
RF
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics*; D001839:Bombesin / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D007476:Ionophores; D000001:Calcimycin; D007655:Ketoglutarate Dehydrogenase Complex; D001839:Bombesin; D001920:Bradykinin; D002118:Calcium